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Malignant Pleural Mesothelioma Co-Opts BCL-XL and Autophagy to Escape Apoptosis

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Malignant Pleural Mesothelioma Co-Opts BCL-XL and Autophagy to Escape Apoptosis Xu et al. Cell Death and Disease (2021) 12:406 https://doi.org/10.1038/s41419-021-03668-x Cell Death & Disease ARTICLE Open Access Malignant pleural mesothelioma co-opts BCL-XL and autophagy to escape apoptosis Duo Xu1,2, Shun-Qing Liang1,2, Zhang Yang1,2, Haitang Yang 1,2,RémyBruggmann 3, Simone Oberhaensli3, Sabina Berezowska 4,ThomasM.Marti1,2,SeanR.R.Hall1,2, Patrick Dorn1,2,GregorJ.Kocher1,2,RalphA.Schmid1,2 and Ren-Wang Peng 1,2 Abstract Escape from programmed cell death is a hallmark of cancer. In this study, we investigated the anti-apoptotic mechanisms and explored the therapeutic potential of BCL-2 homology domain-3 (BH3) mimetics in malignant pleural mesothelioma (MPM), a lethal thoracic malignancy with an extreme dearth of treatment options. By implementing integrated analysis of functional genomic data of MPM cells and quantitative proteomics of patients’ tumors, we identified BCL-XL as an anti-apoptotic driver that is overexpressed and confers an oncogenic dependency in MPM. MPM cells harboring genetic alterations that inactivate the NF2/LATS1/2 signaling are associated with increased sensitivity to A-1155463, a BCL-XL-selective BH3 mimetic. Importantly, BCL-XL inhibition elicits protective autophagy, and concomitant blockade of BCL-XL and autophagic machinery with A-1155463 and hydroxychloroquine (HCQ), the US Food and Drug Administration (FDA)-approved autophagy inhibitor, synergistically enhances anti-MPM effects in vitro and in vivo. Together, our work delineates the molecular basis underlying resistance to apoptosis and uncovers an evasive mechanism that limits response to BH3 mimetics in MPM, suggesting a novel strategy to target this aggressive disease. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction in MPM have revealed frequent oncogenic events Malignant pleural mesothelioma (MPM) is a highly enabled by genetic alterations that inactivate tumor aggressive malignancy that is etiologically associated suppressor genes, most often BRCA1 associated protein- with asbestos exposure1,2. Despite the restriction of 1(BAP1), neurofibromatosis type 2 (NF2), large tumor asbestos use in most countries, the incidence of MPM is suppressor kinase 2 (LATS2), and cyclin-dependent still rising due in part to the long latency (around 40 kinase inhibitor 2 A/2B (CDKN2A/2B), which, however, years) of the interval from carcinogen exposure to tumor have proven difficult to be therapeutically exploited2,5,6. onset3. There are no typical clinical symptoms of Further exacerbating the dilemma, platinum-based che- mesothelioma in the early phase, and the majority of motherapy, the current standard of care for inoperable patients (80%) are diagnosed at advanced stages asso- late-stage MPM, only marginally improves patient sur- ciated with extremely poor prognosis4. Previous studies vival7. Hence, there is a pressing need to identify new druggable targets in MPM and develop effective ther- apeutic strategies for the daunting disease. Correspondence: Ralph A. Schmid ([email protected]) or Ren- The NF2 tumor suppressor gene encodes Merlin Wang Peng ([email protected]) (Moesin-ezrin-radixin-like protein), which mediates 1Division of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland tumor suppression and contact-dependent inhibition by 2Department for BioMedical Research (DBMR), University of Bern, Bern, repressing Hippo, mTORC1, RAS, EGFR, and FAK-Src Switzerland signaling pathways8. The Hippo signaling, an evolu- Full list of author information is available at the end of the article These authors contributed equally: Duo Xu, Shun-Qing Liang, Zhang Yang tionally conserved pathway that regulates organ size and Edited by N. Barlev © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Xu et al. Cell Death and Disease (2021) 12:406 Page 2 of 14 tissue homeostasis by restricting cell growth and pro- regularly tested free of mycoplasma (Microsynth). A- moting apoptosis, is one of the best characterized Merlin/ 1155463 (Cat. #CS-5398), hydroxychloroquine (Cat. NF2-regulated pathways9. Besides the mutation in NF2, #CS-8017), Venetoclax (Cat. #S8048), and ABT-263 other components of the Hippo pathway, e.g., large tumor (Cat. #S1001) were obtained from ChemScene and suppressor kinase 1/2 (LATS1/2), are also frequently SelleckChem, respectively. Bafilomycin A1 was provided inactivated in MPM patients6. Dysregulation of the Hippo by K. Krempaska (Department for Biomedical Research, pathway constitutively activates Yes-associated protein University of Bern, Switzerland). (YAP), a transcription regulator that promotes the tran- scription of genes involved in cell proliferation and anti- Cell viability and clonogenic survival assay apoptosis by interaction with TEA/ATTS domain (TEAD) Cell viability was measured by acid phosphatase (APH) transcription factors10. assay as described18,20. Each data point was generated in Resistance to apoptosis, a critical barrier of tumor triplicate from three independent experiments (n = 3). development, is one of the most prominent hallmarks of IC50 values were determined based on the best-fit curve cancer11. Overexpression of pro-survival B-cell lymphoma generated in GraphPad Prism [log (inhibitor) vs. nor- 2 (BCL-2) family members (BCL-2, BCL-XL, MCL-1, malized response]. Combination Index (CI) was calcu- BCL-W,BCL-B, and BFL-1) is a key apoptosis evasion lated by ComboSyn software21. CI < 1.0, synergism; CI = mechanism that promotes tumor growth by keeping pro- 1.0, additive effects, CI > 1.0, antagonism. Clonogenic apoptosis effectors (BAX/BAK) in check11. By contrast, the assay was done as described18,20. Briefly, cells seeded in BCL-2 homology domain-3 (BH3)-only proteins (BAD, 6-well plates (1000–2000 cells/well) were treated for 96 h BIM, BID, NOXA, PUMA, BIK, BMF, and HRK) induce and cultured in the absence of drugs for 10–12 days apoptosis by neutralizing the pro-survival BCL-2 pro- depending on growth rate. The resulting colonies teins12. As such, targeting anti-apoptotic regulators with were stained with crystal violet (0.5% dissolved in 25% BH3 mimetics represents an attractive strategy for cancer methanol). 13 therapy . Several BH3 mimetics, e.g., the BCL-2/BCL-XL/ BCL-W inhibitor ABT-263 (navitoclax), BCL-2–selective Immunoblotting and immunohistochemistry inhibitor venetoclax (ABT-199), and BCL-XL–selective Cell lysates were prepared and immunoblot analysis was inhibitor A-1155463, have showed promising clinical performed as described18,22. In brief, protein lysates were activity14. In particular, venetoclax has been approved by resolved by SDS-PAGE (Cat. #4561033; Bio-Rad Labora- the US Food and Drug Administration (FDA) for the tories) and transferred onto nitrocellulose membranes treatment of chronic lymphocytic leukemia (CLL) with a (Cat. #170-4158; Bio-Rad). After incubation with blocking 17p-deletion or TP53 mutation15. We and others have buffer (Cat. #927-4000; Li-COR Biosciences) for 1 h at reported that MPM cells can acquire anti-apoptotic room temperature, membranes were incubated with pri- adaptation as a protective mechanism to evade onco- mary antibodies (BCL-XL: 1:1000, #2764; Cleaved Cas- – genic stress and anticancer therapy16 18. In this study, we pase-7: 1:1000, #9491; LC3B: 1:500, #12741; Beclin-1: systematically analyzed the cell survival dependency on 1:1000, #3495; p62: 1:500, #5114; ATG5:1:1000, #12994; anti-apoptotic BCL-2 proteins and explored the potential Cell Signaling Technology) overnight at 4 °C. IRDye of specific BH3 mimetics as anti-MPM therapy. 680LT-conjugated goat anti-mouse IgG (Cat. #926- 68020) and IRDye 800CW-conjugated goat anti-rabbit Materials and methods IgG (Cat. #926-32211) from Li-COR Biosciences were Cell culture and reagents used at 1:10000 dilutions. Signals of membrane-bound Human normal mesothelial cells (LP-9) was a gift from secondary antibodies were visualized by the Odyssey Robert Kratzke (Masonic Cancer Center, University of Infrared Imaging System (Li-COR Biosciences), followed Minnesota, USA)19 and cultured in Medium 199 (Cat. by quantification using Image J23. #M7528; Sigma-Aldrich) supplemented with 15% fetal Immunohistochemical study were performed as bovine serum (Cat. #10270-106; Life Technologies), 1% described24. In brief, surgically removed xenograft tumors penicillin/streptomycin solution (Cat. #P0781, Sigma- (two tumors/group) were formalin-fixed, paraffin- Aldrich), 10 ng/ml of epidermal growth factor (Cat. embedded (FFPE), and stained with hematoxylin and #E5036, Sigma-Aldrich), and 0.4 μg/ml hydrocortisone eosin (H&E) using standard protocols. FFPE tissue blocks (Cat. #07904, STEMCELL TECHNOLOGIES) at 37 °C
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